According to the World Health Organization, Non-Hodgkin?s Lymphoma (NHL) is diagnosed in nearly 70,000 Americans per year. Signals from the B-cell receptor are inappropriately activated in NHL, including in Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL). 90% of CLL tumors patients respond to treatment with ibrutinib, an inhibitor of Bruton?s Tyrosine Kinase (BTK), however in >60% of those cases, the therapy eventually fails. Upon failure, patients are refractory to other targeting strategies and tumor progression becomes rapid, leading to short survival times. Our preliminary data show that long-term ibrutinib treatment of lymphoma cell lines and primary tumors leads to selection for cells that reproducibly exhibit: increased production of reactive oxygen species, decreased phosphatase activity, and up-regulation of DNA repair pathways. Based on this data, we hypothesize that treatment of a subset of CLL and MCL tumors with ibrutinib results in reproducible metabolic changes that lead to increased reactive oxygen species, a process that may precede resistance-conferring mutations in BTK. We hypothesize that ibrutinib-driven increases in reactive oxygen species are responsible for oxidation and inhibition of tyrosine phosphatases and for oxidation of guanine, leading to increased DNA damage. Finally, we believe that these ibrutinib-driven alterations can be also be targeted, and that doing so could result in regained disease control or prevention of acquired resistance. To test these hypotheses we will (1) develop sensitive protein-based assays to monitor molecular indicators of ibrutinib resistance including alterations in reactive oxygen species (2) investigate the impact of modulating ibrutinib-driven reactive oxygen species in CLL cell lines and tumor cells, and (3) comprehensively catalog cell signaling and drug sensitivity changes initiated by ibrutinib in primary CLL and MCL tumor cells isolated longitudinally from patients. We hypothesize that: a) by monitoring these changes we can help to predict which subjects are most likely to develop acquired resistance to ibrutinib; and b) direct targeting of this altered signaling program will lead to the development of combinatorial or sequential therapies enabling improved response. Ultimately, we propose that monitoring this altered signaling program will determine, for a given patient, which additional therapies are likely to be successful if given in combination or sequence with ibrutinib.